Analgesia has historically been achieved in the central nervous system by opiates and analogs which are addictive, and peripherally by cyclooxygenase inhibitors that have gastric side effects. Substance P antagonists induce analgesia both centrally and peripherally. In addition, substance P antagonists are inhibitory of neurogenic inflammation.
The neuropeptide receptors for substance P (neurokinin-1; NK-1) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow, Pharmacol. Rev., 1983, 35, 85-141&gt;. The NK1 and NK2 receptor subtypes are implicated in synaptic transmission (Laneuville et al., Life Sci. 42:1295-1305 (1988)).
The receptor for substance P is a member of the superfamily of G protein-coupled receptors. This superfamily is an extremely diverse group of receptors in terms of activating ligands and biological functions. In addition to the tachykinin receptors, this receptor superfamily includes the opsins, the adrenergic receptors, the muscarinic receptors, the dopamine receptors, the serotonin receptors, a thyroid-stimulating hormone receptor, a luteinizing hormone-choriogonadotropic hormone receptor, the product of the oncogene mas, the yeast mating factor receptors, a Dictyostelium cAMP receptor, and receptors for other hormones and neurotransmitters (see A. D. Hershey, et al., J. Biol. Chem., 1991, 226, 4366-4373).
Substance P (also called "SP" herein) is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH.sub.2. In addition to SP the known mammalian tachykinins include neurokinin A and neurokinin B. The current nonmenclature designates the receptors for SP, neurokinin A, and neurokinin B as NK-1, NK-2, and NK-3, respectively.
More specifically, substance P is a pharmacologically-active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence that is illustrated below:
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH.sub.2 (Chang etal., Nature New Biol. 232, 86 (1971); D. F. Veber etal., U.S. Pat. No. 4,680,283).
Neurokinin A possesses the following amino acid sequence:
His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH.sub.2. PA0 Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH.sub.2. PA0 R.sup.1b is selected from the group consisting of: PA0 R.sup.2a and R.sup.2b are independently phenyl, either unsubstituted or substituted with one or two substitutents selected from the group consisting of: PA0 X.sup.1 is --N, --CH or O, and if X.sup.1 is O, R.sup.1a is absent; PA0 X.sup.2 is --N or --CH; PA0 R.sup.3 is selected from the group consisting of: PA0 R.sup.4 is H or is independently selected from the definitions of R.sup.3 ; PA0 R.sup.5 is C.sub.1-6 alkyl either unsubstituted or substituted with one or more substituents selected from the group consisting of: PA0 R.sup.6 is --H or is independently selected from the definitions of R.sup.5 ; or PA0 R.sup.5 and R.sup.6 can be joined together to form with the nitrogen to which they are attached --N(CH.sub.2 CH.sub.2)L, wherein L is selected from: PA0 R.sup.7 is C.sub.1-6 alkyl substituted with one or more substituents selected from the group consisting of: PA0 R.sup.8 is H, C.sub.1-6 alkyl or is independently selected from the definitions of R.sup.7 ; PA0 R.sup.9 is --CH.sub.2 -phenyl, wherein the phenyl is either unsubstituted or substituted with one or more substituents selected from the group consisting of: PA0 R.sup.10 is --(C.sub.1-6 alkyl)-phenyl, wherein the phenyl is either unsubstituted or substituted with one or more substituents selected from the group consisting of: PA0 R.sup.11 is C.sub.1-6 alkyl, or is independently selected from the definitions of R.sup.10. PA0 R.sup.1a and R.sup.1b are independently H, C.sub.1-8 alkyl or phenyl, either unsubstituted or substituted with --Cl, --Br, --I, --F, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; PA0 R.sup.2a and R.sup.2b are independently phenyl, either unsubstituted or substituted with one or two substitutents selected from the group consisting of: PA0 R.sup.3 is --CONR.sup.7 R.sup.8 ; PA0 R.sup.4 is H or is independently selected from the definitions of R.sup.3 ; PA0 R.sup.7 is C.sub.1-6 alkyl substituted with one or more substituents selected from the group consisting of: PA0 R.sup.8 is H, C.sub.1-6 alkyl or is independently selected from the definitions of R.sup.7 ; PA0 R.sup.10 is --(C.sub.1-6 alkyl)-phenyl wherein the phenyl is either unsubstituted or substituted with one or two substitutents selected from the group consisting of: PA0 R.sup.11 is C.sub.1-6 alkyl, or is independently selected from the definitions of R.sup.10. PA0 R.sup.1a and R.sup.1b are independently H, C.sub.1-8 alkyl or phenyl, either unsubstituted or substituted with --Cl, --Br, --I, --F, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; PA0 R.sup.2a and R.sup.2b are independently phenyl, either unsubstituted or substituted with one or two substituents selected from the group consisting of: PA0 R.sup.3 is --CO.sub.2 R.sup.9 ; PA0 R.sup.4 is H or is independently selected from the definitions of R.sup.3 ; PA0 R.sup.9 is --CH.sub.2 -phenyl, wherein the phenyl is either unsubstituted or substituted with one or more substituents selected from the group consisting of: PA0 R.sup.1a and R.sup.1b are independently H, C.sub.1-8 alkyl or phenyl, either unsubstituted or substituted with --Cl, --Br, --I, --F, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; PA0 R.sup.2a and R.sup.2b are independently phenyl, either unsubstituted or substituted with one or two substituents selected from the group consisting of: PA0 R.sup.3 is C.sub.1-6 alkyl substituted with one or more substituents selected from the group consisting of: PA0 R.sup.5 is C.sub.1-6 alkyl either unsubstituted or substituted with one or more substituents selected from the group consisting of: PA0 R.sup.6 is --H or is independently selected from the definitions of R.sup.5 ; or PA0 R.sup.5 and R.sup.6 can be joined together to form with the nitrogen to which they are attached --N(CH.sub.2 CH.sub.2)L, wherein L is selected from: PA0 R.sup.4 is H or is independently selected from the definitions of R.sup.3. PA0 R.sup.1b is selected from the definitions of R.sup.1a ; PA0 R.sup.2a and R.sup.2b are independently phenyl, either unsubstituted or substituted with one substitutent selected from the group consisting of: PA0 R.sup.3 is selected from the group consisting of: PA0 R.sup.4 is H ; PA0 R.sup.7 is C.sub.2-4 alkyl substituted with one substituent selected from the group consisting of: PA0 R.sup.8 is H, C.sub.1-6 alkyl or is independently selected from the definitions of R.sup.7 ; PA0 R.sup.10 is --(C.sub.1-4 alkyl)-phenyl, wherein the phenyl is either unsubstituted or substituted with one or more substituents selected from the group consisting of: PA0 R.sup.11 is C.sub.1-6 alkyl, or is independently selected from the definitions of R.sup.10.
Neurokinin B possesses the following amino acid sequence:
Substance P acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R. C. A. Frederickson et al., Science, 199, 1359 (1978); P. Oehme et al., Science, 208, 305 (1980)) and plays a role in sensory transmission and pain perception (T. M. Jessell, Advan. Biochem. Psychopharmacol. 28, 189 (1981)). For example, substance P is believed inter alia to be involved in the neurotransmission of pain sensations [Otsuka et al, "Role of Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 &lt;published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as a Pain Transmitter?" TIPS (December 1987) 8 506-510]. In particular, substance P has been shown to be involved in the transmission of pain in migraine (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982)), and in arthritis (Levine et al. Science, (1984) 226 547-549). These peptides have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease, ulcerative colitis and Crohn's disease, etc. (see Mantyh et al., Neuroscience, 25 (3), 817-37 (1988) and D. Regoli in "Trends in Cluster Headache" Ed. F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85-95).
It is also hypothesized that there is a neurogenic mechanism for arthritis in which substance P may play a role (Kidd et al., "A Neurogenic Mechanism for Symmetric Arthritis" in The Lancet, 11 Nov. 1989 and Gronblad et al., "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (1988) 15(12) 1807-10). Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis (O'Byrne et al., in Arthritis and Rheumatism (1990) 33 1023-8). Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions (Hamelet et al., Can. J. Pharmacol. Physiol. (1988) 66 1361-7), immunoregulation (Lotz et al., Science (1988) 241 1218-21, Kimball et al., J. Immunol. (1988) 141 (10) 3564-9 and A. Perianin, et al., Biochem. Biophys, Res. Commun. 161, 520 (1989)) vasodilation, bronchospasm, reflex or neuronal control of the viscera (Mantyh et al., PNAS (1988) 85 3235-9) and, possibly by arresting or slowing .beta.-amyloid-mediated neurodegenerative changes (Yankner et al., Science, (1990) 250, 279-82) in senile dementia of the Alzheimer type, Alzheimer's disease and Downs Syndrome. Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et. al., poster to be presented at C.I.N.P. XVIIIth Congress, 28th June-2nd July, 1992, in press]. Antagonists selective for the substance P and/or the neurokinin A receptor may be useful in the treatment of asthmatic disease (Frossard et al., Life Sci., 49, 1941-1953 (1991); Advenier, et al., Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992)).
In the recent past, some attempts have been made to provide peptide-like substances that are antagonists for substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases listed above. See for example European patent applications (EPO Publication Nos. 0,347,802, 0,401,177 and 0,412,452) which disclose various peptides as neurokinin A antagonists. Similarly, EPO Publication No. 0,336,230 discloses heptapeptides which are substance P antagonists useful in the treatment of asthma. Merck U.S. Pat. No. 4,680,283 also discloses peptidal analogs of substance P.
Certain inhibitors of tachykinins have been described in U.S. Pat. No. 4,501,733, by replacing residues in substance P sequence by Trp residues.
A further class of tachykinin receptor antagonists, comprising a monomeric or dimeric hexa- or heptapeptide unit in linear or cyclic form, is described in GB-A-2216529.
The peptide-like nature of such substances makes them too labile from a metabolic point of view to serve as practical therapeutic agents in the treatment of disease. The non-peptidic antagonists of the present invention, on the other hand, do not possess this drawback, as they are expected to be more stable from a metabolic point of view than the previously-discussed agents.
It is known in the art that baclofen (S-(aminoethyl)-4-chlorobenzenepropanoic acid) in the central nervous system effectively blocks the excitatory activity of substance P, but because in many areas the excitatory responses to other compounds such as acetylcholine and glutamate are inhibited as well, baclofen is not considered a specific substance P antagonist. Pfizer WIPO patent applications (PCT Publication Nos. WO 90/05525, WO 90/05729, WO 91/18899, WO 92/12151 and WO 92/12152) and publications (Science, 251, 435-437 (1991); Science, 251, 437-439 (1991); J. Med Chem,, 35, 2591-2600 (1992)) disclose 2-arylmethyl-3-substituted amino-quinuclidine derivatives which are which are disclosed as being useful as substance P antagonists for treating gastrointestinal disorders, central nervous system disorders, inflammatory diseases and pain or migraine. A Glaxo European patent application (EPO Publication No. 0,360,390) discloses various spirolactam-substituted amino acids and peptides which are antagonists or agonists of substance P. A Pfizer European patent application (EPO Publication No. 0,436,334) discloses certain 3-aminopiperidive derivatives as substance P antagonists. A Pfizer WIPO patent application (PCT Publication No. WO 92/06079) discloses fused-ring analogs of nitrogen-containing nonaromatic heterocycles as useful for the treatment of diseases mediated by an excess of substance P. A Sanofi publication (Life Sci., 50, PL101-PL106 (1992)) discloses a 4-phenyl piperidine derivative as an antagonist of the neurokinin A (NK2) receptor. A Du Pont Merck WIPO patent application (PCT Publication No. WO 92/12128) discloses certain piperidine and pyrrolidine compounds as analgesic agents. A Pfizer WIPO patent application (PCT Publication No. WO 92/15585) discloses 1-azabicyclo-[3.2.2]-nonan-3-amine derivatives as substance P antagonists. U.S. Pat. Nos. 4,804,661 and 4,943,578 disclose certain piperazine compounds as analgesics. U.S. Pat. No. 5,064,838 discloses certain 1,4-disubstituted piperidinyl compounds as analgesics. EPO Publication 0,499,313 discloses certain 3-oxy and 3-thio azabicyclic compounds as central nervous system stimulants. PCT Publication No. WO 92/01679 discloses certain 1,4-disubstituted piperazines useful in the treatment of mental disorders in which a dopaminergic deficit is implicated. Certain phenylacetylpiperazines have been disclosed as peripherally selective kappa-opoid receptor antagonists (Birch, et. al., Bioorg. & Med. Chem. Lett., 2(10), 1275-1278(1992)).
Calcium channel blocking agents are a known group of drugs which act to inhibit transfer of calcium ions across the plasma membrane of cells. It is known that the influx of calcium ions into certain cells in the mammalian body, including the vascular smooth muscle cells and myocardial cells, participates in the activity of such cells and that the administration of calcium channel blockers (also known as calcium antagonists or calcium entry blockers), which inhibit such influx, would suppress myocardial contractile force and rate and cause vasodilation. Calcium channel blockers delay or prevent the cardiac contracture which is believed to be caused by an accumulation of intracellular calcium under ischemic conditions. Calcium overload, during ischemia, can have a number of additional adverse effects which would further compromise the ischemic myocardium. These include less efficient use of oxygen for ATP production, activation of mitochondrial fatty acid oxidation, and possibly, promotion of cell necrosis. Calcium channel blockers are, therefore, useful in the treatment or prevention of a variety of diseases and disorders of the heart and vascular system, such as angina pectoris, myocardial infarction, cardiac arrhythmia, cardiac hypertrophy, coronary vasospasm, hypertension, cerebrovascular spasm and other ischemic disease. In addition, certain calcium channel blocking agents are capable of lowering elevated intraocular pressure when administered topically to the hypertensive eye in solution in a suitable ophthalmic vehicle.
Also, certain calcium channel blockers sensitize multidrug resistant cells to certain chemotherapeutic agents and are useful in the reversal of multidrug resistance by enhancing the efficacy of various anticancer agents (J. Biol Chem., 262 (5), 2166-2170 (1987); Scientific American, 44-51 (March 1989)). In addition, certain calcium channel blockers are suggested as having activity in blocking calcium channels in insect brain membranes and so are useful as insecticides (EMBO J., 8(8), 2365-2371 (1989)).
A number of compounds having calcium channel blocking activity are known, for example certain dihydropyridine derivatives, such as nifedipine and nicardipine, and other compounds such as verapamil, diltiazem and flunarizine.
Some compounds of chemical structures somewhat similar to those of the compounds of the present invention have been reported in U.S. Pat. Nos. 4,089,958 and 4,138,564. However, they are reported as chemical intermediates only.
Some 1,4-bis(diphenylacetyl)piperazines (without substituents on the piperazine ring carbons) have been disclosed as analgesic, antipyretic, and antiinflammatory agents and CNS depressants (U.S. Pat. No. 3,288,795). The preparation of 1,4-bis(diphenylcarbamoyl)piperazine has been reported [D. E. Rivett and J. F. K. Wilshire, Australian J. Chem., 19, 165 (1966)]. Unsymmetrical 1-acyl-4-(diphenylcarbamoyl)piperazines and 1-acyl-4-(dialkylcarbamoyl)piperazines have also been described [L. Korzycka, et al., Pol. J, Pharmacol. Pharm., 38, 545 (1986); L. Toldy, et al Acta Chim. Acad. Sci. Hung., 70, 101 (1971)]. All of these are unsubstituted on the piperazine ring carbons.
Certain 1,4-diacylpiperazine-2-carboxylates and related derivatives in which at least one of the acyl groups is substituted benzoyl have been disclosed as platelet-activating factor antagonists (U.S. Pat. No. 4,923,870 and European Patent Publication 0,368,670). Methyl 4-(benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylate has been reported as an intermediate (EP 0,368,670), as has methyl 1-(benzyloxycarbonyl)-4-tert)-butoxycarbonyl)piperazine-2-carboxylate and the coresponding acid [C. F. Bigge, et al., Tetrahedron Lett., 30, 5193 (1989).